N-ketoalkyl-p-aminobenzoates



i atented Jan. 13, 195 3 2,625,562 N-KETOALKYL-p-AMINOBENZOATES.

David I. Weisblat, Barney J. Magerlein, and

Stanley T. Rolfson, Kalamazoo, Mich., assignors to The Upjohn Company,Kalamazoo, Mich a corporation of Michigan No Drawing. Application July31, 1948,

Serial No. 41,889

15. Claims. (Cl. 260-470) This invention relates toN-(ketopropyD-paminobenzoate compounds, particularly to such compoundswherein the ketopropyl group is a 2-ketopropyl group having asubstituent on the third carbon atom thereof, and to a method use- *fulin their preparation.

" The N-(2-ketopropyl) -p-aminobenzoate compounds of the invention havethe generic formula I a-onzooOnt-p000 Nncnomongoommn' wherein R is fromthe group consisting of hydrogen and the alkyl radicals, n is from thegroup consisting of zero and the positive integers 1 to 7, inclusive, Zis from the group consisting of hydrogen and the arylsulfonyl radicalsand R is from the group consisting of a halogen and the hydroxy, alkoxy,aryloxy, aralkoxy and acyloxy radicals. The term halogen as used hereinis limited to chlorine, bromine and iodine.

In the naming of compounds of the invention and of other compoundsmentioned herein when both a glutamic acid residue and a p-aminobenzoicacid residue are included in the molecule, the nitrogen atom of theglutamic acid residue is, for convenience, herein referred to by thesymbol N and the nitrogen atom of the p-aminoben zoic acid residue isreferred to by the symbol N. In the structural formulae given herein andin the appended claims aromatic nuclei are represented by one or moresimple hexagons. As indicated by the generic formula given, compoundscontaining more than oneglutamic acid or ester residue contemplatedbythe invention are those wherein only the gamma-carboxyl groups areinvolved in the peptide linkages.

The N-(2-ketopropyl)-p-aminobenzoate compounds are useful asintermediates in the preparation of certain compounds referred tobroadly in the art as folio acids. Thus, as described and claimed in aconcurrently filed co-pending application, Serial No. 41,882, now U. S.Patent No. 2,558,711, diethyl N'-(N-(3-hydroxy-2-ketopropyl) ptoluenesulfonyl p aminobenzoyl) glutamate, which can be prepared by themethod of the present invention, can be condensed with2,4,5-triamino-6-hydroxypyrimidine to form diethyl N (N-((Z-amino--hydroxy-G-pteridyl) methyl) -p toluenesulfonyl p aminobenzoyl)glutamate. The latter compound, upon treatment with hydrogen bromide inan aliphatic acid medium, and in the presence of a bromine ac- 'ceptorto prevent bromination of the benzene nucleus of the aminobenzoic acidresidue, according to the method described and claimed in a concurrentlyfiled co-pending application, Serial No. 41,883, now U. S. Patent No.2,562,222, and after subsequent hydrolysis of the ester groups, isconverted to N'- (N- (2-amino-4-hydroxy-6-pteridyl) -methyl-p-aminobenzoyl) -glutamic a c i d (pteroylglutamic acid) generallyrecognized, when the glutamic acid residue has the same configuration as1(-'..') -glutamic acid, as being identical with the "L. casez' factoror vitamin Bo from liver. When N (N-(3-hydroxy -2-ketopropyl)-p-aminobenzoyl) -glutamic acid is condensed with 2,4,5-triamino-6-hydroxypyrimidine, pteroylglutamic acid is formed directlywithout the necessity of splitting a sulfonyl radical from the productwith hydrogen bromide or of hydrolyzing ester groups. In similarfashion, other N-(2-ketopropy1) -paminobenzoate compounds of theinventioncan be condensed with 2,4,5-triamino-6-hydroxypyrimidine toform th corresponding 2-amino-4- hydroxy-fi-pteridyl compounds of thefolic acid type in the manner just described.

It should be mentioned that certain of the N-(2-ketopropyl) paminobenzoate compounds wherein R of the formula given is an acyloxygroup having a plurality of carbon atoms, e. g. certain of theN-(3-acy1oxy-2-hydroxypropyl)-paminobenzoate compounds, often do notcondense as smoothly with 2,4,5-triamino-6-hydroxypyrimidine as does theformoxy and the non-acyloxy N (2-ketopropyl)-p-aminobenzoate compoundsdescribed herein and for this reason they can with advantage behydrolyzed to the corresponding hydroxy compounds, 1. e. to theN-(3-hydroxy-2- ketopropyl) p aminobenzoate compounds, and the latterthen condensed with 2,4,5-triamino-6- hydroxypyrimidine in the mannermentioned when such condensation product is desired.

COOR

mCHgCHOHCH2TCO(NH( 011201120 o'),.o R

reaction mixture.

C O O R hologram-SEC O CHz-N-C CO(NHAHCHECHZOOLDR' IIIN-(3-halo-2-ketopropyl):p-aminobenzoate compound i alkali C O O B.HO-CHzC O CHz-NC C O (NHHCHzCHzC O),.O R Q N- (3-l1ydroxy-2-ketopropyl)-p-amlnobenzoate Icompoun'd [alkanol O O O R ac 1ox -ornooom-N- o oNricHomo H2 0), 0 R

N-(3-acyloxy-2-ketopropyl)-p-aminobenzoate compound Certain of the newN-(2-ketopropyl) -p-'aminobenzoate compounds of the invention, 1. e. theN- (3-R -2-ketopropyl) -p-aminobenzoate compounds having the formula(II) in the accompanying diagram wherein R and n have the values givenpreviously and R' is from the group consisting of chlorine, bromine andiodine and thealkoxy, aryloxy, aralkoxy "and acyloxy radicals, canbe'prepared by oxidizing an N-(3-R""-2- hydroxypropyl) p aminobenzoatecompound having the formula (I) with 'chromic acid. The N- (3-R"-2-ketopropy1) -p-aminobenzoate ompound (II) is formed readily and inhigh yield and can be isolated without difficulty from the The reactionisgenerally carried out by subjecting the N-(3-R"'-2-hydroxypropyl) epaminobenzoate compound to the action of chromic anhydride in an inertsolvent. A mixture of an alkali metal dichromate and a mineral acid,such as sulfuric acid, jean often be used in the place of chromicanhydride, if desired. Although glacial acetic acid is'the'preierredsolvent,

"other suitable solvents can be used, such as acetone'and propionic orvaleric acids. A small proportion, e.'g.'irom 5 to per cent or less, ofwater can often be included in the mixture, ii desired. A solution ofthe N-(3+R"-2-hydroxypropyl) -paminobenzoate compound (I) and of chromicanhydride in acetic acid can be prepared and allowed to stand'iorseveral hours at from about 0 to about 30C., or somewhat higher, or theN-(3-R"%2-hydroxypropyl) p amino-benzoate compound can be addedgradually to a solution or chromic anhydride in acetic acid. Reactionusually occurssmoothly at ordinary room temperatures, or somewhat below,but the mixture can, in certain instances, be warmed gently, if desired.

The reaction is usually substantially complete in from one to severalhours and the N-(3-R"'-2- ketopropyl) -p-aminobenzoate compound can berecovered by diluting the reaction mixture with water and extracting thediluted mixture with ethyl acetate, etheror other suitable solvent. Theextract is dried after washing with water or dilute aqueous sodiumbicarbonate, depending upon whether it contains carboxy or carboxylicester groupspand the ether or other solvent then distilled. TheN-(3-R"'-ketopropyl) -p-aminobenozate compound is thus obtained as asolid residue which is usually sufficiently pure for further use butwhich can, if desired, be purified 'N (2-ketopropyl) -p-aminobenz0atecompounds having the formula (VI) 0 o o R I R -omCQom-NH-Ooomnonomomc o,0 R

usually without isolating the arylsulfonyl-containing compound from theacetic acid reaction mixture, ifdesired. The reaction is carried outconveniently by mixing the arylsulfonyl compound, hydrogen bromide and abromine acceptor,

such as phenol, catechol or naphthol, in an anhydrous aliphatic acidmedium, usually at ordinary room temperature. Several molar proportionsof hydrogen bromide are'usually employed. After standing for asufficient length of time, usually from a few minutes to afew hours,-themixture can be poured into ether or petroleum naphtha and thhydrobrornide of the free amine recovered by filtering. Other convenientand apparent ways of recovering the-amine or itshydrobromide can beemployed.

Many of the N (3 R' 2 lzetopropyl) paminobenzoate compounds "and thefree amines obtained as just described are crystalline or amorphous,white or yellowish solids, which can be purified by crystallizing from asuitable solvent. Other of the compounds are oily in nature. They formcrystalline semi-carbazones and other normal ketone derivatives.

Certain of the N (3 2 ketopropyl) p-aminobenzoate compounds, i. e theN-(S-halo- 2 ketopropyl) p --aminobenzoate compounds (III), andparticularly the N (3 acyloxy --2- -l :etopropyl) p aminobenzoatecompounds (V) and also the corresponding free amines, can be sponding N-3-hydroxy 2eketopropyl) -p-aminobenzoate compound (IV) is preferablycarried out by treating the halogen-containing compound withapproximately one chemically equivalent proportion of an aqueous oralcoholic alkali, such as aqueous barium carbonate, dilute aqueous oralcoholic sodium hydroxide, or aqueous or alcoholic potassium carbonate.The reaction is carried out conveniently by stirring a mixture of thereactants at ordinary room temperature for from one to several'hours.Soluble alkalies should be added to the mixture at approximately therate at which they are consumed.

The conversion of an N-(3-acyloxy-2-ketopropyl).-p-aminobenzoatecompound (V) to an N (3 hydroxy 2 ketopropyl) p aminobenzoate compound(IV) .isaccomplished conveniently byester interchange using an .alkanol,preferably vusing'the same alkanol from which any carboxylic esterradicals. in the molecule are derived. 'The reactionis carried out byheating, usually byrefluxing, a solution of the acyloxyketo compound inan excess, e. g. in from about 5 to about 20 molarproportions or more,of all sanol. The inclusion of an ester interchangeketopropyl)-p-aminobenzoate compound (IV) or free amine remains as acrystalline or syrupy residue which is usually sufiiciently pure forfurther use. Purification can be efiected using Girards reagent P. or T.to yield the keto compounds in solid form.

As indicated by the generic formula (VII), N- (2-ketopropyl)-p-aminobenzoate compounds containing more than one glutamic acid orester residue contemplated by the invention are those wherein only thegamma-carboxyl groups are involved in the peptide linkages, such as theresidues derived from N-(p-aminobenzoyl) -gammaglutamylglutamic acid,N'-(p-aminobenzoyl)- gamma-glutamyl-gamma-glutamylglutamic acid, and thelike. Preferred compounds of the invention are those wherein nrepresents the integer 1, i. e. those containing one glutamic acid orester residue, and the invention will be described with particularreference thereto.

Compounds similar to, or identical with, those of the folic acid groupmade by using compounds of the invention as intermediates, such aspteroylglutamic acid and pteroyl-gamma-glutamylgamma-glutamylglutamicacid, which are of greatest value as measured by their biologicalactivity against Lactcbaczllus casei or Streptococcus fecalis R, arethose wherein the glutamic acid residues possess the same configurationas l(i) -glutamic acid. However, the invention also contemplatescompounds having the dextro configuration as well as racemic mixtures.

N- (2-ketopropyl) -p-aminobenzoate compounds wherein Z of the genericformula (VII) represents an arylsulfonyl radical are of particular valuebecause of the protection afiorded the aromatic amino group by thearylsulfonic group. Compounds having the amino group thus protected areoften not subject to decomposition and the formation of by-products whenemployed as a reactant, e. g. when condensed with 2,4,5-triamino-G-hydroxypyrimidine, to nearly the same extent as are compoundsin which the aro matic amino group is unprotected. Following thecarrying out of a reaction using an N-(Z-ketopropyD-p-aminobenzoatecompound containing such an arylsulfonylamino group, the 'arylsulfonylradical can be split readily from the molecule formed, as mentionedpreviously, by treating the compound with hydrogen bromide in analiphatic acid medium and in the presence of a bromine acceptor.

Although the invention is described in the case of arylsulfonylcompounds with particular reference to p-toluenesulfonyl compounds, itis understood that the invention contemplates compounds andintermediates containing other arylsulfonyl radicals, such as theo-toluenesulfonyl, benzenesulfonyl, and naphthalenesulfonyl radicals aswell as many others. Arylsulfonylradicals having substituents, such aschlorine, bromine, or a nitro group, on the aromatic nucleus can also beused provided only that the substituent is non-reactive underthereaction conditions. The preferred arylsulfonylradical is thep-toluenesulfonyl radicalbecause the com pounds formed are generallywell defined 'crystalline solids and because it has been found thathigher yields of amines are often formed when splitting a'p-toluenesulfonylamino compound than when splitting certain otherarylsulfonyl derivatives of the same amino compound. It should bementioned, furthermore, that the method involved in the presentinvention can be carried out and the corresponding final compoundsprepared using starting compounds wherein the arylsulfonyl group isreplaced by an alkylsulfonyl, aralkylsulfonyl or cycloalkylsulfonylgroup such as the methanesulfonyl, alphatoluenesulfonyl orcyclohexylsulfonyl radical respectively.

Although benzoic acid ester or glutamic acid ester residues present incertain of the compounds of the invention can comprise an alkyl ester,such as the methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert.-butyl,amyl, lauryl, dodecyl and many other esters, the preferred ester is theethyl ester due to matters of convenience and economy.

Although the invention is directed particularly, in case of esters ofthe glutamic acid residues, to alkyl esters, the process of theinvention can also be carried out and corresponding compounds preparedusing other esters, such as the phenyl, tolyl, xylyl, cyclohexyl, benzyland many other aryl, aralkyl or cycloalkyl esters.

N (3 R"-2-hydroxypropyl) p-aminobenzoate compounds (I) which can beoxidized to the corresponding keto compounds by the method of theinvention include compounds wherein, as mentioned previously, the symbolR" presents chlorine, bromine, iodine or the alkoxy, aryloxy, aralkoxyor acyloxy radicals. Alkoxy compounds which can be used include themethoxy, ethoxy, n-propoxy, iso-propoxy, amyloxy compounds and manyothers. Aryloxy compounds which can be used include the phenoxy,tolyloxy, naphthoxy compounds and many others. .Aralkoxy compounds whichcan be used include the phenylmethoxy, phenylethoxy, naphthlymethoxy,tolylethoxy compounds and many others. Cycloalkoxy compounds, such asthe cyclohexoxy compounds, can also be used, if desired.

The N-(3 R 2 hydroxypropyD-p-aminobenzoate compounds which can beoxidized by the method of the invention can be prepared conveniently, asdescribed and claimed in a concurrently filed co-pending application,Serial No. 41,884, by first reacting an epihalohydrin, i. e.epichlorohydrin, epibromohydrin or epiiodohydrin, with a p-aminobenzoatecompound having the following formula (VIII) COOR' aryl-SOz :N-(3l1alo-2-hydroxypropyl)-p-aminobenzoate compound wherein Xrepresentschlorine, bromine oriodine.

7 The N (3-halo-2-hydroxypropyl)-p-aminoben@- zoate compound can then betreated with dilute alkali to remove hydrogen halide and form an N (2,3epoxypropyD-p-aminobenzoate compound having the following formula (X)COOR aryl 02 N-(2,3epoxypropyl)-D-aminobenzoate compound The epoxycompound can then be-react'ed with ametal salt ofan alcohol or phenol orwith a carboxylic acid to form an N-(3-alkoxy-2-hydroxypropyl)-p-aminobenzoate compound, an N (3aryloxy-2-hydroxypropyl)p-aminobenzoate compound or anN-(3-acyloxy-2-hydroxypropyl) -p-aminoben'zoate compound, respectively.By using a metal salt-of an aralkanol an N-(3- aralkoxy 2hydroxypropyl)-p-aminobenzoate compound is formed readily.

The paminobenzoate compounds (VIII) wherein n is an integer from thegroup 1 to '7, inclusive, can be obtained as described and claimed in aconcurrently filed co-pending application, Serial No. 41,883. Accordingto the method of the co-pending application, a paminobenzoate compoundhavin one glutamic acid residue in the molecule is prepared by reactingglutamic acid or an alkyl ester thereof with anarylsulfonyl-paminobenzoyl halide or with a p-nitrobenzoyl halide. Thehalides referred to in this connection are the chlorides and bromides.When a p-nitrobenzoyl halide is used an N'-(pnitrobenzoyl) -glutamicacid or ester is first obtained which, upon reduction, e. g. withhydrogen using platinum oxide as a catalylst, yields an N'-paminobenzoyl)-glutamic acid or ester. The

latter compound can be converted readily by means of an arylsulfonylhalide to an N-(arylsulfonyl-p-aminobenzoyl)-glutamic acid or ester.When an arylsulfonyl-p-aminobenzoyl halide is reacted with glutamic acidor its ester, an N-(aryl'sulionyl p aminobenzoyll-glutamic acid or esteris formed directly; Furthermore, N-(p-aminobenzoyl) -glutamic acid andthe N'- (arylsulfonyl-p-aminobenzoyl)-glutamic acids can, if desired, beconverted to the corresponding alkyl esters, e. g., by treatment with analkanol and an esterification catalyst in known manner, or the esterscan be hydrolyzed to the corresponding acids. In similar manner, otherp-aminobenzoate compounds can be prepared having up to seven glutamicacid residues in the molecule by starting with the correspondinggammaglutamylglutamic acids or esters containing the requisite number ofpeptide linkages.

Certain advantages of the invention are apparent from the followingexamples which are given by way of illustration only and are not to beconstrued as limiting.

Eaample 1 .-Diethyl. N (p-nitrobenzoyl) -1 glutamate One houndred elevengrams of p-nitrobenzoyl chloride was added at about 0 C. over a periodof about one hour to a solution of 95.8 grams of crud diethyl l(+)-glutamate hydrochloride and 80 milliliters of pyridine in 200milliliters of benzone. The mixture was stirred for five hours,extracted first with dilute hydrochloric acid and then with aqueoussodium bicarbonate and the benzene removed under reduced pressure. Theresidue'icon'sisted ofllllgrams of a pasty; neutral fraction consistinglargely of diethyl N'-(p-- nitro-benzoyl)-1-glutamate. Afterrecrystallization from dilute ethanol, the ester melted at 93 to 95 C.It had a specific rotation of (a) =-18 in 95 per cent ethanol. Thesodium bicarbonate extract upon acidification yielded 42 grams ofp-nitrobenzoic acid.

Example 2.Diethyl N-(p-amz'nobenzoyl) -1- glutamate Crude diethylN-(p-nitrobenzoyl) -1-glutamate prepared as in Example 1 was dissolvedin ethanol and reduced with hydrogen under a pressureof about 40 poundsper square inch using platinum oxide as acatalyst. The mixture was thenfiltered to recover platinum and the ethanol evaporated under reducedpressure. There was thus obtained a 52 per cent yield of diethylN-(paminobenzoyl) -l-glutamatemelting at to 138 C. Uponrecrystallization from dilute ethanol, the ester melted at 140 to 141 C.and had a specific rotation (a) =-9.5 in 95 per cent ethanol.

Ana-1.: Calcd. for C16H2205N2: C, 59.6; H, 6.9; N, 8.7. Found: C, 59.6;H, 6.8; N, 9.0.

Example 3.Dzethyl N '-(p-toluenesuljo'nyl-paminobenzog/Z) -glutamatcThirty and nine-tenths grams of p-toluenesulfonyl-p-aminobenzoylchloride and 23.9 grams of diethyl1(+) -glutamate hydrochloride weredissolved in 300 millilitersof ethylene dichloride and the solutioncooled to between 0 and 10 C. The cold solution was stirred vigorouslyand 22.3 grams of triethylamine in 72 milliliters of ethylene dichloridewas added slowly over a period of about 20 minutes. The temperature ofthe mixture was held between 10 and 20 C. during the addition of thetriethylamine and the mixture then allowed to stand at room temperaturefor one hour. The mixture was then washed successively with Water,dilute hydrochloric acid, saturated aqueous sodium bicarbonate andfinally with water. The colorless solution thus obtained was dried withanhydrous sodium sulfate and naphtha was added until the solution becameopalescent. The mixture was then cooled to cause crystallization andfiltered. The crystals, after drying, consisted of 36 grams of diethylN-(ptoluenesulfonyl p aminobenzoyl) -l-glutamate meltin at 124 to 126 C.

Example 4.Diethyl N'-(p-toZuenesuZfonyZ-paminobenzoyl) -1 -glutamate Amixture of 407 grams of p-toluenesulfonyl-paminobenzoic acid and 3,450milliliters of toluene was dried by distilling the mixture until 350milliliters of distillate had been collected. A few drops of pyridineand 50 milliliters of thionyl chloride was then added to the dry toluenesolution and the mixture stirred and refluxed for one-half hour. Thesolution was then cooled with agitation for two hours and the solidwhich precipitated was recovered by filtering and washing with tolueneand then-with mixed hexanes and drying. There was thus obtained 387grams ofp-toluenesulfonyl-p-aminobenzoyl chloride melting at 141 r0142"C.

A mixture of 48 grams of diethyl 1(-I) glutamate hydrochloride, 68 gramsof p-toluenesulionyl-p-aminobenzoyl chloride, 19' grams of magnesiumoxide, 250 milliliters of ethylene dichloride and 100 milliliters ofwater was stirred with coolingfor about e hours'. The mixture wasfilteredand the organic l'ayerwas separated from Example 5.--D2'ethyl N(N (3-chZoro-2-hydroxyprom Z) -p-toluenesulfonyl p aminobenaoyl)glutamate A mixture of 2.85 grams of diethylN'-(ptoluenesulfonyl-p-'aminobenzoyl) -glutamate and 1.1 grams ofepichlorohydrin was agitated at 135 C. Two drops of pyridine were addedand agi-' tation at 135 C. was continued for five minutes. The excessepichlorohydrin was volatilized under reduced pressure. The residuewhich consisted of diethyl N'-(N- (3-chloro-2-hydroxypropyl)-ptoluenesulfonyl-p-aminobenzoyl) -glutamate was used in subsequentexperiments without further purification.

Diethyl N (N (3-bromo-2-hydroxypropyl) -ptoluenesulfonyl-p aminobenzoyl)glutamate is prepared in similar fashion using epibromohydrin instead ofepichlorohydrin.

Example 6.Ethyl N (3 -chloro 2 hydroxypropyl)-p-toluenesulfonyZ-p-aminobenzoate A mixture. of five grams of ethylp-toluene.-, sulfonyl-p-aminobenzoate and 3.4 milliliters ofepichlorohydrin was heatedat 135 C. and two drops of pyridine added. Avigorous action ensued and after five minutes the mixture was cooled,dissolved in 50 milliliters of ethanol and treated three timeswith'decolorizing carbon. The ethyl N-(3-chloro 2 hydroxypropyl)ptoluenesulfonyl p aminobenzoate which I remained upon volatilization ofthe ethanol and excess epichlorohydrin in vacuo was used in sub--sequent reactions without further purification.

toluenesulfonyl-p-aminobenzoyl)-glutamate A mixture consisting of about1.3 grams of diethyl N-(N-(3-chloro 2 hydroxypropyl)ptoluenesulfonyl-p-aminobenzoyl)-glutamate, 20 milliliters of methylethyl ketone, 0.17 gram of sodium bi-carbonate and 3 milliliters ofwater was refluxed for 410 minutes. The methyl ethyl ketone and waterwere then distilled in vacuo.

and the residue taken up in a mixture of ether and water containing asmall proportion of alco'-" 1101. The ether layer was separated,washedwithcold dilute sulphuric acid and then with water and saturatedsodium bicarbonate solution and finally twice with water and once withsaturated sodium chloride solution. The washed solution was filteredthrough anhydrous sodium sulfate and the ether distilled in vacuo. Theresidue consisted of 0.98 gram of diethyl N'-(N(2,3-

epoxypropyl) -p toluenesulfonyl p aminoben Z yD-glutamate in the'form ofa light brown 1' oil.- This is a yield cat-87.5 per cent of thetheoretical amount.

The epoxypropyl compound obtained as just described and other epoxycompounds described in the examples were a$s l7 d $91 epoxy contentbythe following procedure:

of absolute ethanol and 20 milliliters of a 0.1

to 0.15 normal standardized solution of hydrogen chloride in ether wasadded. After standing at room temperature for two hours, 30 to 10milliliters of water was added to the mixture and the unreacted hydrogenchloride titrated with standardized alkali. The hydrogen chlorideconsumed was a measure of the amount of epoxy compound present. Whenanalyzed in this manner, the crude epoxypropyl compound was shown tocontain 49.4 per cent ofepoxy compound.

-When the above procedure was carried out using dilute ethanol insteadof methyl ethyl ketone, there was obtained a per cent yield of productwhich upon assay for epoxy. content proved to be per cent-pure diethylN-(N-(2,3- epoxypropyl) -p toluenesulfonyl p aminobenzoyD-glutamate.

When the procedure was carried out using anhydrous potassium carbonateand anhydrous methyl ethyl ketone there was obtained a 72 per cent yieldof product which upon assay was found to contain 42.8 per cent ofdiethyl N'-(N-(2,3- epoxypropyl) -p toluenesulfonyl p aminobenzoyl)-glutamate.

Example 8.Ethyl N-(2,3-epomypropyl) W0 enesuZfonyZ-p-aminobenzoate In amanner similar to thatdescribed .in Example 7, ethylN-i3-chloro-2-hydroxypropyl) -ptoluenesulfonyl-p-aminobenzoate wastreated,

with anhydrous potassium carbonate in an hydrous methyl ethyl ketone.refluxed two hours. From the mixture there was isolated a productcontaining 33 'per cent of ethyl N- (2,3-epoxypropyl)-p-toluenesulfonyl-p-aminoa benzoate. r

When the process was repeated using sodium bicarbonate and diluteethanol instead of anhydrous potassium carbonate and anhydrous meth-,

yl ethyl ketone and the mixtures refiuxed'for thirty minutes, the crudeproduct obtained contained 46.4 per cent of ethyl N '(2,3 -epoxypr'opyl)p-toluenesu1ionyl-p-aminobenzcate.

Example 9.Ethyl N-(S-benao Jy- Z-hydrOryprO- pyl) -p-toluenesulfonyl-pemium)enzoate A mixture of 1.88 grams of ethyl N- (2,3-epoxypropyl)-p-toluenesulfonyl-p-arninobenzoate and 0.61 gram of benzoic acidwas heated at C.

and one drop of pyridine added to the agitatedmelt. Heating wascontinued for about two hours, the melt becoming so thick afteraboutfifteen minutes that it could no longer bestirred.

Upon cooling, the melt hardened to a glass-like solid. The. reactionmixture was dissolved in 20 milliliters of n-butanol and the solutiondiluted with mixed hexanes until it became opalescent. The solution wasallowed to'stand at room temperature for three days and the crystalswhich separated were recovered by filtering, washing with abutanol-hexane mixture and drying in vacuo over sulfuric acid.- Therewas'thus ob.- tained 1.56 grams of ethyl N-(3-benzoxy-2-hydroxypropyl)-p-toluenesulfonyl-p-a.minobenzoate which after crystallizing. twice.frornn-butanol...

melted at l33.5 to'135.5 C. J

AnaL: and. for czfiuz' bmsi (3.62.765 n, 5.47. Found: C', 62.38; H,5.28. I if Example 10.-Ethyl N- (3-formoary-2hildroxy prom/l)-p-toZuenesuZfomuZ-p-aminobenzoatev A mixture consisting of 11.1 gramsof ethyl N- One gram of the epoxy compound was dissolved in fivemilliliters The mixture was.

(2,3 epoxypropyl) p toluenesulfonyli-p-aminobenzoate, 1.57 grams offormic acid and three drops of pyridine washeated at about 100 C. withstirring for two hours. The reaction mixture which. contained "ethyl N-(3-formoxy-2-hydroxypropyl)-p-toluenesulfonyl-p-aminobenzoate wasoxidized without isolation of the ester directly to the corresponding2-ketopropyl compound.

Example 11. N 3-metho:cy-2-hydrozcypropyl)p-toluenesuZfonyZ-p-aminobenzoic acid A mixture of 1.1 grams of ethylN-(2,3epoxypropyl) p toluenesulfonyl-p-aminobenzoate, 122 milliliters ofmethanol and 0.34 gram of sodium methoxide was allowe'dtostand at roomtemperature for three hours and then refluxed for one hour. The mixturewas then cooled, diluted with water and extracted with .10 millilitersof ether. Acidification of the extracted aqueous solution withhydrochloric acid gave a precipitate which, after filtering and drying,consisted of 0.94 gram of N (3-methoxy-2-hydroxypropyl)-p-toluenesulfonyl-p-aminobenzoic acid melting at 152 to 158 C. Afterrecrystallization from methanol, the product melted at 157 to 159 C. Ithad a neutral equivalent of 360 as compared with the calculated value of379.

Example 12. Diethyl N '-(N-(3-pheno:cy-2-hydrorypropyl)p-toluenesulfonyl-p-aminobenzoyl -1 -glutamate A mixture of 14.3 gramsof diethyl N-(p-'toluenesulfonyl -'p -aminobenzoyl)-1g1utamate, 4.5grams of 1,2-epoxy-3-phenoxypropane and 3 drops of pyridine was heatedat 140 C. for 30 minutes and then cooled. The viscous mass was dissolvedin benzene and the solution'washed with dilute mineral acidand then withwater and dried over'sodium'sulfate. Volatilization of the benzene invacuo gave 19.7 grams of diethyl N'- (N- 3-phenoxy-2-hydroxypropyl)-p-toluenesulfonyl-p-aminobenzoyl) -1-glutamate as a 'viscous, yellowoil.

Example i3.--'--Diethyl N'--(N-(3-chZcro-2-ketopropyl) ptoluenesulfonyl-p-aminobenzoyl) glutamate The oily diethylN-(N-(3-chloro-2-hydroxypropyl) -p -toluenesulfonyl-p-aminobenzoyl)-glutamate prepared from 2.85 grams of diethyl N'- (ptoluenesulfonyl-p-aminobenzoyl) glutamate and an excess ofepichlorohydrin' was dissolved in milliliters of glacial acetic acid. Amixture of 0.8 gram of chromic anhydride, 18 milliliters of glacialacetic acid and .l'milliliter of water was added slowly with stirringand cooling. The mixture was allowed to stand atroom temperature fortwelve hours and the acetic acid then volatilized under reducedpressure. Theresidue was taken up in a'mixture of water and ether andthe layers separated. The ether layer was washed with water untilthewashings were no longer green and then treated with charcoal and driedover anhydrous magnesium sulfate. Upon distillation of the ether, thereremained diethyl N- (N (3 chloro-Z-ketoprop'yl)-p-toluenesulfonylp-aminobenzoyl) -glutamate as a pale yellowviscous'oil.

Example 1 4.--Ethyl N (3-chZoro-2-ketopropyl)p-toluenesuZfonyZ-p-aminobeneoate The crude oily ethylN-(3-chloro-2-hydroxypropyl) -p-toluenesulfony1-p-aminobenzoate preparedfrom grams of ethyl 'p-toluenesulfonylp-aminobenzoate and an excess ofepichlorohydrin was dissolved in150milliliters of acetic acid and "amixture. of.12 grams'ofisodium dichromate, 10 milliliters of sulfuricacid, 45 milliliters of water and 60 milliliters of acetic acid wasadded over a period of three hours while maintaining the mixture at 5 C..After stirring for an additional three hours, the oxidation mixture wasdiluted with" water and extracted with ether. The ethereal extract waswashed with sodium bicarbonate and the ether distilled. The residue ofethyl N-(3-chloro-2-ketopropyl)-p-toluenesulfonyl-p-aminobenzoatecrystallized from dilute ethanol on prolonged standing. The crystallizedproduct weighed 5.5 gramsand after two crystallizations from diluteethanol, melted at 106 to 113 C.

Anal: Calcd'for CiHzoOsNSCl: C, 55.7; 4.9; C1, 8.7. Found: 0, 56.0; H,4.9; Cl, 6.1.

Example 15.--N-(3-chZ0ro-2-Icetopropyl)-p-toluenesuZfonyL-p-aminobenzoic acid A solution of one gram'of-N-(3-chlorc-2-hydroxypropyl)-p-toluenesulfony1 -paminobenzoic acidin five'milliliters of acetic acid was added to a solution of'0.35 gramof chromic anhydride in a mixture of 10 milliliters of acetic acid and0.2milliliter of water. The mixture was allowed to stand at roomtemperature overnight and the acetic acid then distilled in vacuo. Theresidue was taken up in ethyl acetate and the ethyl acetate solutionwashed with water and sodium bicarbonate and the ethyl acetate thendistilled in vacuo. Crystallization of the residue from dilute ethanolgave 0.54 gram of crystalline N (3'-chloro-2-ketopropyl)-p-toluenesulfonylp-aminobenzoio acid melting at 154to 158 C.

Example 16.-Ethyl N-(.i-beneoary-ZJaetopropyl)-p-toZuenesuZfonyZ-p-aminobenzoate A mixture of 1.8 grams of chromicanhydride, 5 milliliters of water and '50 milliliters of acetic acid wasadded at 18' C. over a period of one hour to asolution of ethylN-(3-benzoxy-2- hydroxypropyl) p toluenesulfonyl p aminobenzoatein .250milliliters of glacial acetic acid. The mixture was allowed to stand atroom temperature for 24 hours and the acetic acid distilled in vacuo.The residue was taken up in a mixture of ethyl acetate and water and thelayers separated. The ethyl acetate layer was washed with water toremove chromium salts and then with dilute aqueous sodium bicarbonate toremove acetic acid. The ethyl acetate was then distilled in vacuo andthe residue Was crystallized from iso-propanol. There was thus obtained4.74 grams of crystalline ethyl N-(3- benzoxy-2-ketopropyD-ptoluenesulfonyl p aminobenzoate melting at 59 to 72 C. After repeatedcrystallization from iso-propanol, the product melted at 70 to 73 C. Thesemi-carbazone decomposed at to C. when heated slowly.

Anal: Calcd. for CzsHzsO'rNsi C, 63.0; H, 5.1. Found: C, 63.1; H, 5.2.

prom Z) p toluenesulfonyl p aminobenformoxy .2 -lhydroxypropyl) ptoluenesul-i fonyl-paminobenzoyl) -g1utamate, 50 milliliters of aceticacid and 2.1 grams of chromic anhydride was heated for two hours at 24to 30 C. The reaction mixture was then diluted with 500 milliliters ofwaterand extracted twice with.

benzene. The combined benezene extracts were washed three times withwater and then dried over anhydrous magnesium sulfate. The mixture wasfiltered to remove magnesium sulfate and the benezene distilled invacuo. There was thus obtained 6.8 grams of a, light yellow, oilyresidue of diethyl N'-(N-(3-formoxy-2-ketopropyl) p toluenesulfonyl paminobenzoyD- glutamate.

Example 18.Ethyl N-(3'-formo:cy-2-lcetopropyl) p tolaenesalfonyl paminobeneoate A mixture of 4.4 grams of chromic anhydride, 200milliliters of acetic acid and the ethyl N (3 formoxy 2 hydroxypropyl) ptoluenesulfonyl-p-aminobenzoate prepared from formic acid and 11.1 gramsof ethyl N-(Z, 3- epoxypropyl) p toluenesulfonyl p aminobenzoate wasstirred for one hour during which time the temperature rose to 30 C. Theacetic acid was then distilled in vacuo and the residue triturated withether. The mixture was centrifuged and the precipitate washed twice withether. The combined ethereal solution and washings were washedsuccessively with water, sodium bicarbonate solution and water and thendried with anhydrous magnesium sulfate. Evaporation of the ether left aresidue of 7.91 grams of ethylN-(3-formoxy-2-ketopropyl)-ptoluenesulfonyl-p-aminobenzoate as an oilhaving an index of refraction N :1.546.

Example 19.-Dz'ethyl N'-(N-(3-acetoa:y-2-Icetoglutamate A mixture wasprepared consisting of 8.85 grams of diethylN'-(N-(3-acetoxy-2-hydroxypropyl) p toluenesulfonyl paminobenzoyD-glutamate having an index of refraction N :1.5396, 50milliliters of glacial acetic acid and milliliters of propionic acid.The mixture was cooled to 0 C. and a solution of 1.65 grams of chromicanhydride in a mixture of 1.5 milliliters of water and 30 milliliters ofglacial acetic acid was added slowly with stirring. The mixture wasallowed to stand at about 5 C. for twelve hours and the solvent thendistilled under reduced pressure. The residue was treated with a mixtureof water and ether and the layers sep-- arated. The ether layer waswashed twice with saturated sodium chloride solution then with saturatedsodium bicarbonate solution and again with saturated sodium chloridesolution. The washed ethereal solution was then dried with anhydrousmagnesium sulfate and the ether distilled. There was thus obtained-6.1grams of yellowish oily diethyl N'-(N- (3-acetoxy2-ketopropyl) -ptoluenesulfonyl p 'aminobenzoyl) -glutamate.

Example 20.-N (S-methoay-Z-ketopropyl)-ptoluenesaljonyZ-p-aminobenzoicacid A solution of 0.33 gram of chromic anhydride in 0.5 milliliter ofwater and 3 milliliters of acetic acid was added to a solution of 0.95gram of N-- (3 methoxy 2 hydroxypropyl) p toluenesulfonyl-p-aminobenzoicacid in milliliters of acetic acid. The mixture was allowed to standovernight at room temperature and the acetic acid then distilled invacuo. There was thus obtained a green syrup from which N-(3-methoxy- 2ketopropyl) p toluenesulfonyl p aminobenzoic acid was isolated. I

:14 Example 21.-Diethyl N (N (3-phenoay-2 -ketoprom l) -p-aminobenzoyl)-1 -glatamate A solution of 6.2 grams of chromic oxide in 25 millilitersof water was added over a period of ten minutes and at a temperature ofabout 3 C. to a solution of diethyl N -(N-(3-phenoxy-2-hy droxypropyl)-p-amin'obenzoyl) -1-glutamate in a mixture of 215 milliliters of aceticacid and 60 milliliters of propionic acid. The mixture was allowed tostand at about 3 C. for twenty hours and then poured into water and theaqueous mixture extracted with benzene. The layers were separated andthe benzene layer was washed several times with water and dried overanhydrous sodium sulfate. Benzene was distilled from the dried solutionin vacuo after which there remained 17.5 grams of diethylN'-(N-(3-phenoxy- 2 ketopropyl) -p-aminobenzoyl) -1-glutamate as a brownresinous oil having an index of refraction N =1.545.

Example 22.--Diethyl N -(N-(3-metho.ry-2-ketopropyl) -p-tolaenesalfonylp aminobeneoyl) glutamate A solution of 0.536 gram of chromic oxide inabout 5 milliliters of water was added slowly at 20 C. and with stirringto a solution of 2 grams of diethyl N '-(N (3-methoxy-2-hydroxypropyl)p-toluenesultonyl-p-aminobenzoyl) -1-glutamate in 19 milliliters ofglacial acetic acid. The mixture was allowed to stand for three andone-half hours and was then poured into water and extracted withbenzene. The benzene layer was washed thoroughly with water and thebenzene vaporized in vacuo. There was thus obtained a residue consistingof 1.3 grams of diethyl N -(N- (3-meth-oxy-2-ketopropyl)-p-toluenesulfonyl-paminobenzoyl)-1-g1utamate having an index ofrefraction N =L544O and melting at 82 to 84 C.

Example 23.-Diethyl N (N- (S-methoay-Z-lcetopropyl)-p-tolaenesalfonyl-p-aminobeneoyl) -1- glutamate A mixture was preparedconsisting of 70 milliliters of acetic acid, 20 milliliters of propionicacid and 4.95 grams of diethyl N-(N-(3-methoxy-2- hydroxypropyl)-p-toluenesulfonyl-p-aminoben- ZoyD-I-gIutam-ate. The mixture was cooledat 3 C. and a solution of 1.17 grams of chromic anhydride in 10milliliters of water Was added. The mixture was allowed to standat'about 3 C. for seventeen hours then poured into a mixture of 200milliliters of water and milliliters of benzene. After thoroughagitation, the benzene layer was separated and washed with diluteaqueous sodium bicarbonate. Evaporation ofthe benzene from the washedbenzene layer left a residue consisting-of 4.1 grams of syrupy diethyl N(N-(3-methoxy-2 ketopropyl)-p-toluenesulfonyl-p-aminobenzoyl)-1-g1utamate; Recrystallization of thesyrup from dilute ethanol gave a crystalline product melting at 82 to 84C.

Example 24.Ethyl N-(3-hydroxy-2-ketopropyl) -10-tolaenesuljonyl-p-aminobeneoate One gram of ethyl N-(3-chloro-2-ketopropyl)p-toluenesulfonyl-p-aminobenzoate was dissolved in 20 milliliters ofacetone-and the solution diluted with 10 millilitersof. water. One-halfgram of barium carbonate was thenadded and the mixture stirred overnightat room temper ature and then refluxed for two hours. The mixture wasthen filtered, partially concentrated-refiltered and then concentrated.The thick liquid A solution was prepared consisting of 0.3 gram of ethylN-(3-chloro-2-ketopropyl) p--toluenesulionyl-p-aminobenzoate, 15milliliters of acetone and 3 milliliters of water and 7.5 milliliters of0.1 normal sodium hydroxide solution was added with gentle agitation atroom temperature over a period of one hour. The solution was thendiluted with water and filtered. There was thus obtained 0.1 gram ofsolid ethyl N-(3-hydroxy-2- hetopropyl)-p-toluenesulfonyl-p-aminobenzoate which decomposed over a wide range onheating.

The compound was subsequently condensed with2,4,5-triamino-6-hydroxypyrimidine to form the toluene sulionylderivative of the ethyl ester of pteroic acid.

Example 26.-N- (3-hydroxy-2 -ketopropyz) -p-tcZ-ucnesuZfonyZ-p-aminobeneoic acid Eleven milliliters of 0.1 normal sodiumhydroxide solution was added at room temperature over a period of onehour to an agitated solution or" 0.2 gram ofN-(3-chloro-2-ketopropyl)-ptoluenesulfonyl-p-aminobenzoic acid in 10rnilli liters of acetone and 8 milliliters of water. The rate ofaddition was adjusted so that the pl-l of the solution was at all timesless than 8.5. Ace tone was then distilled in vacuo from the mixture andthe residue extracted with ether. Upon drying the ethereal solution andvolatilizing the ether, there was obtained a non-crystalline residue ofN-(3hydroxy-2-ketopropyl)-p-toluenesulfonyl-p-aminobenzoic acid whichwas used in l a subsequent reaction without further purification.

In similar manner, N-(N- (3chloro-2-lsetopropyl) p toluenesulfony1 paminobenzoyl) glutamic acid is hydrolyzed to N' (N-(B-hydroxy-2-ketopropyl) p toluenesulfonyl-p-aminobenaoyl) -glutamic acid.

Emmple 27 .-Eth'yl N- (3 -hydroxy-2-kctoprc-pggl)p-toZuenesuZfonyZ-p-aminobeneootc A mixture consisting of 3.67 grams ofethyl N- droxide solution and refluxed for fifteen minutes. Uponcooling,the alkaline solution was titrated with 0.5 normal sulfuric acidsolution and it was found that 16.72 milliliters of 0.5 normal sodiumhydroxide had been consumed during the refiuxing. This corresponds tothe presence in the original distillate of 93 per cent of thetheoretical amount of ethyl rormate formed by ester interchange betweenthe ethanol and the N-(3-formoxy 2-ketopropyll -p-toluenesulfcnyl paminobenzoate. The process was repeated and an additional 2.8 per centof ethyl for-mate accounted for in the second distillate bringing thetotal yield of ethyl formate to 95.8 per cent of the theoretical amount.

The residue from .the ethanol ethyl formats The distillate was mixedwith 30 milliliters of 0.5 normal sodium hy- 16 distillation wasconcentrated in vacuo' to remove most of the alcohol and the residuetaken up in ether. The ethereal solution was washed twice with waterthan with suiicient aqueous sodium bicarbonate to remove thep-toluenesulfonic acid and finally with water and dried. Distillation ofthe ether left an oily residue consisting of 3.4 grams of ethylN-(3-hydroxy 2-ketopropyl) p-toluenesulfonyl-p-aminobenzoate having an.index of refraction N :1.550.

Ernample 28.Diethyl N (N (3hydr0my-2-Icetopropyl) -p-toZuene-suZjonyZ-paminobenzoyl) glutamate A mixture of 2.6 grams of diethyl N'-(N(3-acetoxy-2-ketopropyl) p toluenesulfonyl p aminobenzoyl) -glutamate, 0.1gram of p-toluenesulfonic acid and 40 milliliters of absolute ethanolwas refluxed for three hours and then distilled slowly until 25milliliters of distillate had been collected. An additional 40milliliters of absolute ethanol was added and the mixture again refluxedfor 2.25 hours. The mixture was then concentrated in vacuo and thesyrupy residue taken up in ether and washed successively with 3 portionsof water and one portion of saturated sodium chloride solution. Theethereal solution was then dried over anhydrous magnesium sulfate andthe ether evaporated in vacuo. There was thus obtained 2 grams ofviscous diethyl N-(N- (3-hydroxy 2 ketopropyl) ptoluenesulfonyl-p-aminobenzoyl) -glutainate having a specific rotationat 25 C. in absolute ethanol or -1S.

Example 29.Ethyl N (3-chZoro-2-Icetopropyl) p-aminobeneoate-hydrobromideA mixture was prepared consisting of 0.5 gram of ethylN-(3-chloro-2-ketopropyl) -N- (p-toluenesulfonyl)-p-aminobenzoate, 0.235gram of phenol and 5 milliliters of a 25pm cent solution of hydrogenbromide in glacial acetic acid. The mixture was allowed to stand for 2hours at room temperature and then poured into 40 milliliters of dryether. The mixture was filtered and the crystalline residue washed withdry ether and then dried. There was thus obtained 0.0! gram of ethyl N-(3-chloro 2 ketopropyl) -paminobenzoate hydrobromide. This product,when condensed with 2,4,5-triamino-6-hydroxypyrimidine, yielded aproduct having a marked activity for Streptococcus fecalis R.

Example 30 Inamanner similar to that described in ample 29 thep-toluenesulionyl radical is split- 17 We claim: 1. The method whichincludes oxidizing a compound having the formula o o R ac1oxy-cmononcm-Nooomncnomomoo)"011' ary1S O 2 wherein R is a member ofthe class consisting of hydrogen and the alkyl radicals, n is a memberof the class consisting of zero and the positive integer 1 and whereinthe acyloxy radical is the acyloxy radical of a carboxylic acid withchromic acid in an inert water-soluble solvent to form a compound havingthe formula COOR acyloxy oHZoo CH1 r iccomncncnomcmnos aryl-SO:

wherein R n have the values iven.

2. The method of claim 1 wherein the oxidation is carried out in aceticacid as a reaction medium.

3. The method which includes oxidizing an alkyl N-(3 acyloxy2-hydroxypropyl) p-arylsulfonyl-p-aminobenzoate wherein the acyloxyradical is the acyloxy radical of a carboxylic acid with chromic acid inan inert water-soluble solvent to form an alkyl N-(3-acyloxy-2-keto-'propyl) -p-arylsulfonyl-p-aminobenzoate.

4. The method which includes oxidizing ethyl N-( 3 benzoxy-Zhydroxypropyl) -p-t0luenesu1- fonyl-p-aminobenzoate with chromic acid inan inert water-soluble solvent at a. temperature between about 0 andabout 30 centigrade to form ethyl N- (3-benzoxy-2-ketopropyl)-p-toluenesulfonyl-p-aminobenzoate.

5. The method which includes oxidizing ethyl N-( 3 formoxy-Zhydroxypropyl) -p-toluenesulfonyl-p-aminobenzoate with chromic acid inan inert water-soluble solvent at a temperature between about 0 andabout 30 centigrade to form ethyl N-(3-formoxy-2-ketopropyl)-p-toluenesulfonyl-p-aminobenzoate.

6. The method which includes oxidizing a dialkyl N(N-3--acyloxy2-hydroxy-propyl) -p-arylsulfonyl-p-aminobenzoyl) glutamatewherein the acyloxy radical is the acyloxy radical of a corboxylic acidwith chromic acid in an inert watersoluble solvent to form a dialkylN'-(N-('3- acyloxy 2 ketopropyl) p arylsulfonyl p aminobenzoyl)-glutamate.

7. The method which includes oxidizing diethyl N'- (N-(3-formoxy-2-hydroxy-propyl)-p-toluenesulfonyl-p-aminobenzoyl)-glutamate with chromic acid in aninert water-soluble solvent at a temperature between about 0 and about30 centigrade to form diethyl N-(N-(3-formoxy-2- ketopropyl) -p-toluenesulfonyl-p-aminobenzoyl) glutamate.

8. The method which includes oxidizing diethyl N (N-3-acetoxy-2-hydroxypropyl) -p-toluenesulfonylp-aminobenzoyl)-g1utamatewith chromic acid in an inert water-soluble solvent at a temperaturebetween about 0 and about 30 centigrade to form diethylN'-(N-(3-acetoxy-2- ketopropyl) -p-toluenesulfonyl-p-aminobenzoyl)glutamate.

9. A compound having the formula wherein R is a member of the classconsisting of hydrogen and the alkyl radicals, n is a member of theclass consisting of zero and the integer 1, Z is a member of the classconsisting of hydrogen and the arylsulfonyl radicals and wherein theacyloxy radical is the acyloxy radical of a carboxylic acid.

10. Diethyl N (N-(3-acetoxy-2-ketopropyl)-ptoluenesulfonyl-p-aminobenzoyl) -glutamate.

ll. Alkyl N-(3-acyloxy-2-ketopropy1) p-arylsulfonyl-p-aminobenzoatewherein the acyloxy radical is the acyloxy radical of a carboxylic acid.

12. Ethyl N (3-benzoxy 2 ketopropyl) ptoluenesulfonyl-p-aminobenzoate.

13. Ethyl N-(3-formoXy-2-ketopropyl) -p-toluenesulfonyl-p-aminobenzoate.

14. Dialkyl N-(N-(B-acyloxy-Z-ketopropyl) -ptoluenesulfonyl paminobenzoyl) glutamate wherein the acyloxy radical is the acyloxyradical of a carboxylic acid.

15. Diethyl N'- (N-( 3-formoxy-2-ketopropyl)p-toluenesulfonyl-p-aminobenzoyl) -glutamate.

DAVID I. WEISBLAT. BARNEY J. MAGERLEIN. STANLEY T. ROLFSO-N.

No references cited.

1. THE METHOD WHICH INCLUDES OXIDIZING A COMPOUND HAVING THE FORMULA